第 50 章受损大脑的修复

在其历史的大部分时间里，神经病学一直是一门诊断严谨但疗效甚微的学科。简而言之，神经学家以其能

够非常精确地定位病变而闻名，但直到最近，他们在治疗方面几乎没有什么可提供的。这种情况现在正在改变。

我们对大脑神经元、神经胶质细胞和突触的结构、功能和化学的理解取得了进展，从而产生了新的治疗思

路。其中许多现在正在进行临床试验，有些已经可供患者使用。由于 3 个主要原因，发育神经科学正在成为这种

巨变的主要贡献者。首先，保存或替换因损伤或疾病而丢失的神经元的努力依赖于我们对控制胚胎中神经细胞

生成和死亡的机制的理解的最新进展（第 45 和 46 章）。其次，改善损伤后神经通路再生的努力很大程度上依赖

于我们对轴突生长和突触形成的了解（第 47 和 48 章）。第三，越来越多的证据表明，一些破坏性脑部疾病，如

孤独症和精神分裂症，是胚胎或出生后早期神经回路形成障碍的结果。因此，对正常发育的研究为准确发现疾

病出了什么问题提供了必要的基础。

在本章中，我们将关注其中的前 2 个问题：神经科学家希望如何增强神经元的有限能力以恢复正常功能。我

们将从描述轴突及其末端与细胞体分离后轴突如何退化开始。切断的轴突再生在哺乳动物的周围神经系统和低

等脊椎动物的中枢神经系统中是强大的，但在哺乳动物的中枢神经系统中非常差。许多研究人员都在寻找这些

差异的原因，希望通过理解它们能够找到促进人脑和脊髓损伤后恢复的方法。事实上，我们将看到哺乳动物神

经元再生能力的几个差异已经被发现，每一个差异都开辟了有前途的新治疗方法。

然后我们将考虑神经损伤的一个更可怕的后果：神经元的死亡。成人大脑无法形成新神经元一直是神经科

学的中心教条，因为先驱神经解剖学家圣地亚哥 · 拉蒙 · 卡哈尔断言，在受损的中枢神经系统中，“一切都可能

死亡，没有任何东西可以再生。”尽管拉蒙 · 卡哈尔补充说：“如果可能的话，未来的科学将改变这一严厉的法

令，但在上个世纪的大部分时间里，这种悲观的观点主导了神经学。”值得注意的是，在过去的几十年里，越来

越多的证据表明神经形成确实发生在成年哺乳动物大脑的某些区域。这一发现有助于加快研究刺激神经形成和

替换损伤后神经元的方法的步伐。一个多世纪后，神经科学家终于开始推翻卡哈尔的“严厉法令”。

50.1 轴突的损伤会影响神经元和邻近细胞

由于许多神经元有很长的轴突和中等大小的细胞体，对中枢或外周神经系统的大多数损伤都涉及轴突的损

伤。通过切割或挤压的方式切断轴突被称为轴突切断术，其后果有很多。

50.1.1 轴突变性是一个活跃的过程

轴突切开术将轴突一分为二：一个仍然附着在细胞体上的近端部分和一个失去了这一关键附着点的远端部

分。轴突切开术破坏了轴突的远端部分，因为在短暂的潜伏期能量供应减少。很快，改变就变得不可逆转了。切

断的神经末梢的突触传递失败，轴突内的钙水平增加。钙激活蛋白酶，启动细胞骨架分解和降解程序，随后发生

轴突的物理退化。如图 50.1.1 所示，一旦去神经支配开始，其进展相对较快并且不可避免地进行至完成。这种退

化反应是精心设计的一系列变化中的第一步，称为华勒氏变性，奥古斯都 · 沃勒最初于 1850 年对其进行了描述。

长期以来，横切轴突的退化被认为是一个被动过程，是与细胞体分离的结果，细胞体的大部分蛋白质都是

在细胞体中合成的。由于缺乏新蛋白质来源，远端残肢被认为会枯萎。如图 50.1.2 所示，但是在小鼠中发现和分

析了一种称为华勒氏慢变性的自发突变，对这种观点提出了挑战。在华勒氏慢变性突变小鼠中，周围神经的远

端残端在横断后持续存在数周，比正常小鼠长约 10 倍。这一非凡的发现表明，退化不是与细胞体分离的被动结

果，而是一种主动调节的反应。

对华勒氏慢变性突变小鼠的分析导致了对该法规性质的深入了解。该突变导致形成突变形式的烟酰胺单核

苷酸腺嘌呤转移酶 1，这是一种参与代谢辅因子烟酰胺腺嘌呤二核苷酸生物合成的酶。通常存在于轴突中的相关

酶烟酰胺单核苷酸腺嘌呤转移酶 2 在轴突切开后变得非常不稳定并迅速分解，导致烟酰胺腺嘌呤二核苷酸的损

失，这对于维持轴突中的能量稳态至关重要。虽然正常的烟酰胺单核苷酸腺嘌呤转移酶 1 局限于细胞核，但突变

50.1 轴突的损伤会影响神经元和邻近细胞

Chapter 50 / Repairing the Damaged Brain 1237

Figure 50–1 Axotomy affects the injured neuron and its

synaptic partners.

A.A normal neuron with an intact functional axon wrapped by

myelinating cells contacts a postsynaptic neuron. The neuron’s

cell body is itself a postsynaptic target.

B.After axotomy, the nerve terminals of the injured neuron

begin to degenerate (1). The distal axonal stump separates

from the parental cell body, becomes irregular, and undergoes

Wallerian degeneration (2). Myelin begins to fragment (3) and

the lesion site is invaded by phagocytic cells (4). The cell body

of the damaged neuron undergoes chromatolysis: The cell

body swells and the nucleus moves to an eccentric position

(5). Synaptic terminals that contact the damaged neuron with-

draw and the synaptic site is invaded by glial cell processes (6).

The injured neuron’s inputs (7) and targets (8) can atrophy and

degenerate.

mammals. Many investigators have sought the reasons

for these differences in the hope that understanding

them will lead to methods for augmenting recovery

of the human brain and spinal cord following injury.

Indeed, we shall see that several differences in regen-

erative capacity of mammalian neurons have been

discovered, each of which has opened promising new

approaches to therapy.

We shall then consider an even more dire conse-

quence of neural injury: the death of neurons. The ina-

bility of the adult brain to form new neurons has been

a central dogma of neuroscience since the pioneering

neuroanatomist Santiago Ramón y Cajal asserted that

in the injured central nervous system, “Everything

may die, nothing may be regenerated.” This pessi-

mistic view dominated neurology for most of the last

century despite the fact that Ramón y Cajal added, “It

is for the science of the future to change, if possible,

this harsh decree.” Remarkably, in the past few dec-

ades, evidence has accumulated that neurogenesis

does occur in certain regions of the adult mammalian

brain. This discovery has helped accelerate the pace

of research on ways to stimulate neurogenesis and to

replace neurons following injury. More than a century

later, neuroscientists are finally beginning to reverse

Cajal’s “harsh decree.”

Damage to the Axon Affects Both the

Neuron and Neighboring Cells

Because many neurons have very long axons and

cell bodies of modest size, most injuries to the cen-

tral or peripheral nervous system involve damage to

axons. Transection of the axon, either by cutting or by

crushing, is called axotomy, and its consequences are

numerous.

Axon Degeneration Is an Active Process

Axotomy divides the axon in two: a proximal segment

that remains attached to the cell body and a distal seg-

ment that has lost this crucial attachment. Axotomy

dooms the distal segment of the axon because energy

supplies dwindle during a short-lived latent period.

Soon the alterations become irreversible. Synaptic

transmission fails at severed nerve terminals, and

calcium levels increase within the axon. The calcium

activates proteases, initiating a program of cytoskeletal

disassembly and degradation, and physical degenera-

tion of the axon ensues. Once the denervation begins,

its progression is relatively rapid and inexorably pro-

ceeds to completion (Figure 50–1). This degenerative

response is the first step in an elaborate constellation

尼氏体

髓磷脂

跨神经元变性

（逆行）

跨神经元

变性

（顺行）

突触末梢回缩

与神经胶质细胞侵袭

染色质溶解

小胶质细胞

-巨噬细胞浸润

髓鞘

碎片

华勒氏

变性

终端变性

少突胶质细胞

或施旺细胞

765432

胶质

细胞

Kandel-Ch50_1236-1259.indd 1237 12/01/21 9:10 AM

图 50.1.1: 轴突切开术影响受伤的神经元及其突触伙伴。A. 具有完整功能轴突并被髓鞘形成细胞包裹的正常神经

元与突触后神经元接触。神经元的细胞体本身就是一个突触后目标。B. 轴索切断术后，受损神经元的神经末梢

开始退化（1）。远端轴突残端与亲代细胞体分离，变得不规则，并发生华勒氏变性（2）。髓磷脂开始碎裂（3），

病变部位被吞噬细胞侵入（4）。受损神经元的细胞体发生色谱分解：细胞体膨胀，细胞核移动到偏心位置（5）。

与受损神经元接触的突触末稍退出，突触部位被神经胶质细胞突侵入（6）。受损神经元的输入（7）和目标（8）

会萎缩和退化。

的华勒氏慢变性形式错误定位到轴突，在那里它替代烟酰胺单核苷酸腺嘌呤转移酶 2 以延长轴突存活。令人惊

讶的是，野生型和华勒氏慢变性形式的烟酰胺单核苷酸腺嘌呤转移酶 1 维持烟酰胺腺嘌呤二核苷酸水平的主要

方式不是通过合成它，而是通过抑制另一种分解烟酰胺腺嘌呤二核苷酸的蛋白质 SARM1。因此，如图 50.1.3A 所

示，SARM 的缺失可以保护受损的轴突，而 SARM1 的激活会导致退化。如图 50.1.3B 所示，其他几种蛋白质调

节该核心通路。

总之，这些激动人心的新发现为以下问题提供了答案：为什么在轴突切开术后，远端残端退化而近端残端

得以保留。远端残端被剥夺了通常从细胞体输送的营养物质的传统解释是不完整的。相反，轴突中的信号通路

会感知损伤并迅速引发退化。在这种情况下，轴突提供的关键元素是烟酰胺单核苷酸腺嘌呤转移酶 2。它在轴突

切开后的分解会抑制 SARM1，并且可能与刺激 SARM1 的因子激活同时发生，从而引发烟酰胺腺嘌呤二核苷酸

的损失，从而导致能量危机，从而导致华勒氏变性。

这些最近的发现可能有助于设计治疗神经系统疾病的方法，在这些疾病中，轴突变性很明显并且通常先于

神经元死亡。运动神经元的致命疾病（肌萎缩侧索硬化症）就属于这一类。其他可能性包括某些形式的脊髓性

肌萎缩症、帕金森病，甚至阿尔茨海默病。在这些疾病中以及在代谢、毒性或炎症损伤后发生的轴突退化类似于

急性创伤后的退化，并且可能以类似的方式进行调节。因此，虽然保存横断的远端轴突的方法不太可能在临床

上用于治疗遭受外伤的患者，但相同的技术可用于治疗神经退行性疾病。

即使轴突的近端部分仍然附着在细胞体上，它也会受到影响。在某些情况下，神经元本身会因细胞凋亡而

死亡，这可能是因为轴突切开术将细胞体与其靶源性营养因子的供应隔离开来。即使这没有发生，细胞体也经

常会经历一系列称为色谱分解反应的细胞和生化变化：如图 50.1.1B 所示，细胞体膨胀，细胞核移动到偏心位置，

粗面内质网变得支离破碎。色谱分解伴随着其他代谢变化，包括蛋白质和核糖核酸合成的增加以及神经元表达

的基因模式的变化。如果重新生成成功，这些更改将被撤销。

50.1.2 轴突切开导致附近细胞的反应性反应

轴突切开术在多种类型的相邻细胞中启动一系列反应。其中最重要的反应是包裹远端神经节段的神经胶质

细胞的反应。一种是髓鞘破碎，然后被吞噬细胞去除。这个过程在周围神经系统中很快，产生髓磷脂的施旺细胞

将髓磷脂分解成小碎片并将其吞没。然后分裂的施旺细胞分泌从血流中募集巨噬细胞的因子。巨噬细胞反过来

1100

50.1 轴突的损伤会影响神经元和邻近细胞

1238 Part VII / Development and the Emergence of Behavior

Figure 50–2 Axonal degeneration is delayed in Wlds

mutant mice.In wild type animals, axons in the distal

stump degenerate rapidly after sectioning of a peripheral

nerve, as shown by disrupted axonal fragments (yel-

low) and the lack of myelinated axonal profiles at the

electron micrographic level. In Wlds mutant mice the

distal portion of severed axons persists for a long time.

(Confocal micrographs reproduced, with permission, from

electron micrographs reproduced, with permission, from

Mack TGA, Reiner M, Beirowski B, et al. 2001. Copyright

of changes, called Wallerian degeneration, that were ini-

tially described in 1850 by Augustus Waller.

The degeneration of transected axons was long

thought to be a passive process, the consequence of

separation from the cell body, where most of the cell’s

proteins are synthesized. Lacking a source of new pro-

tein, the distal stump was thought to simply wither

away. But the discovery and analysis in mice of a spon-

taneously occurring mutation called Wlds (Wallerian

degeneration slow) challenged this view (Figure 50–2).

In Wlds mutant mice, the distal stumps of peripheral

nerves persist for several weeks after transection,

about 10-fold longer than in normal mice. This remark-

able finding suggested that degeneration is not a pas-

sive consequence of separation from the cell body, but

is rather an actively regulated response.

Analysis of the Wlds mutant mice led to insights

into the nature of this regulation. The mutation led to

formation of a mutant form of nicotinamide mononu-

cleotide adenyltransferase 1 (NMNAT1), an enzyme

involved in biosynthesis of a metabolic cofactor, nicoti-

namide adenine dinucleotide (NAD). A related enzyme,

NMNAT2, which is normally present in the axon,

becomes quite unstable and breaks down rapidly fol-

lowing axotomy, leading to loss of NAD, which is criti-

cal for maintenance of energy homeostasis in the axon.

Although normal NMNAT1 is confined to the nucleus,

the mutant Wlds form mislocalizes to the axon, where

it substitutes for NMNAT2 to prolong axonal survival.

Surprisingly, a main way that both the wild type and

Wlds forms of NMNAT maintain NAD levels is not

by synthesizing it but by inhibiting another protein,

SARM1, that breaks down NAD. Thus, loss of SARM

protects damaged axons, whereas activation of SARM1

leads to degeneration (Figure 50–3A). Several other pro-

teins modulate this core pathway (Figure 50–3B).

10 –12

天后

野生型

华勒氏慢变性

突变体

Kandel-Ch50_1236-1259.indd 1238 12/01/21 9:11 AM

图 50.1.2: 华勒氏慢变性突变小鼠的轴突变性延迟。在野生型动物中，远端残端的轴突在周围神经切片后迅速退

化，如轴突碎片（黄色）中断和电子显微水平上缺乏髓鞘轴突轮廓所示。在华勒氏慢变性突变小鼠中，切断轴突

的远端部分会持续很长时间

[432]

。

1101

50.1 轴突的损伤会影响神经元和邻近细胞

Figure 50–3 A core pathway regulates axon degeneration

following axotomy in mice.

A.Damage to neurites in vitro leads to degeneration of the por-

tions separated from the cell body. Likewise, axotomy in vivo

leads to Wallerian degeneration, as shown by loss of myelin

profiles in the cross section. Both in vitro and in vivo axons are

spared if the SARM1 gene is deleted. (From Gerdts et al. 2013.)

B.NMNAT2, closely related to the mutant Wlds protein, is

normally present in axons. It can generate nicotinamide

adenine dinucleotide (NAD) and inhibit SARM1, which

degrades NAD. High NAD levels are required for

energy metabolism, keeping adenosine triphosphate (ATP)

levels high and calcium levels low in the axon. Following

axotomy, NMNAT2 levels decrease rapidly, disinhibiting

SARM1. NAD levels fall, ATP is depleted, calcium levels rise,

calcium-dependent proteases are activated, and the axon is

degraded. Kinases (MAPK) and a ubiquitin ligase (Phr1) regulate

the pathway.

未受损伤受损伤

未受损伤损伤

野生型

体外

野生型

SARM1 KO

轴突

完整性

轴突

运输

2+ LOW

ATP

HIGH

NAD

NMNAT2

NAM

SARM1

OFF

PHR1

MAPK2

NMN

轴突

变性

轴突

损伤

2+ HIGH

ATP

LOW

NAD

NMNAT2

NAM

SARM1

PHR1

MAPK2

NMN

Kandel-Ch50_1236-1259.indd 1239 12/01/21 9:11 AM

图 50.1.3: 一条核心通路调节小鼠轴索切断术后的轴突变性。A. 体外神经突损伤导致与细胞体分离的部分变性。

同样，体内轴突切开术导致华勒氏变性，如横截面中髓鞘轮廓的丢失所示。如果 SARM1 基因被删除，体外和体

内的轴突都会幸免。B. 烟酰胺单核苷酸腺嘌呤转移酶 2 与突变体华勒氏慢变性蛋白密切相关，通常存在于轴突

中。它可以生成烟酰胺腺嘌呤二核苷酸并抑制降解烟酰胺腺嘌呤二核苷酸的 SARM1。能量代谢需要高烟酰胺腺

嘌呤二核苷酸水平，从而使轴突中的三磷酸腺苷水平保持高水平，钙水平保持低水平。轴突切开后，烟酰胺单核

苷酸腺嘌呤转移酶 2 水平迅速下降，从而抑制 SARM1。烟酰胺腺嘌呤二核苷酸水平下降，三磷酸腺苷耗尽，钙

水平升高，钙依赖性蛋白酶被激活，轴突被降解。有丝分裂原活化蛋白激酶和泛素连接酶（Phr1）调节该通路。

1102

50.2 受伤后中央轴突再生不良

帮助施旺细胞处理碎片。施旺细胞还产生促进轴突再生的生长因子，我们稍后会谈到这一点。

相比之下，在中枢神经系统中，形成髓鞘的少突胶质细胞几乎没有或根本没有处理髓鞘的能力，碎片的清

除依赖于称为小胶质细胞的常驻吞噬细胞。这种细胞特性的差异可能有助于解释观察到的华勒变性在中枢神经

系统中进行到完成的速度要慢得多。

轴突切开术还会影响受伤神经元的突触输入和突触目标。当轴突切开术破坏细胞的主要输入时（就像在去

神经肌肉中发生的那样，或者当视神经被切断时在外侧膝状体核中的神经元中发生的情况）后果是严重的。通

常目标会萎缩，有时甚至会死亡。当目标仅部分去神经时，它们的反应更加有限。此外，轴突切开术影响突触前

神经元。在许多情况下，突触末稍从细胞体或染色质神经元的树突中退出，并被神经胶质细胞的过程所取代（外

周的施旺细胞和中枢神经系统的小胶质细胞或星形胶质细胞）。这个过程称为突触剥离，会抑制突触活动并会损

害功能恢复。

尽管突触剥离的机制仍不清楚，但已提出 2 种可能性。一是突触后损伤导致轴突末端失去与突触位点的粘

附性，因此它们随后被胶质细胞包裹。另一个是神经胶质细胞响应受损神经元释放的因子或其细胞表面的变化

而启动突触剥离过程。无论触发因素是什么，轴突切开术对小胶质细胞和星形胶质细胞的激活显然有助于剥离

过程。此外，生化改变的星形胶质细胞，称为反应性星形胶质细胞，有助于在损伤部位附近形成神经胶质疤痕。

由于这些跨突触效应，神经元变性可以在顺行和逆行方向上通过回路传播。例如，严重萎缩的去神经神经

元可能无法激活其目标，从而导致萎缩。同样，当突触剥离阻止传入神经元从其目标细胞获得足够的营养时，传

入神经元的输入就处于危险之中。这种连锁反应有助于解释中枢神经系统某一区域的损伤最终如何影响远离损

伤部位的区域。

50.2 受伤后中央轴突再生不良

中枢神经和外周神经在受伤后的再生能力方面存在很大差异。外周神经通常可以在受伤后得到修复。虽然

外周轴突的远端节段退化，但远端残端周围的结缔组织元素通常存活下来。

如图 50.2.1 所示，轴突芽从近端残端生长，进入远端残端，并沿着神经向其目标方向生长。驱动这一过程的

机制与那些引导胚胎轴突的机制有关。施旺细胞分泌的趋化因子将轴突吸引到远端残端，远端残端内的粘附分

子促进轴突沿细胞膜和细胞外基质生长，神经鞘中的抑制分子防止再生轴突误入歧途。

一旦再生的外周轴突到达它们的目标，它们就能够形成新的功能性神经末梢。运动轴突形成新的神经肌肉

接头；自主神经轴突成功地重新支配腺体、血管和内脏；和感觉轴突重新支配肌梭。最后，那些失去髓鞘的轴突

被重新髓鞘化，并且色谱细胞体恢复了原来的外观。因此，在周围神经系统的所有 3 个部分（运动、感觉和自

动），轴突切断术的影响是可逆的。然而，外围再生并不完美。在运动系统中，力量的恢复可能很大，但精细动

作的恢复通常会受损。一些运动轴突永远找不到它们的目标，一些在不合适的肌肉上形成突触，一些运动神经

元死亡。然而，周围神经系统的再生能力令人印象深刻。

如图 50.2.1 所示，相比之下，中枢神经系统受伤后的再生能力较弱。受损轴突的近端残端可以形成短芽，但

这些短芽很快就会停滞并形成肿胀的末端，称为“回缩球”，无法继续生长。远距离再生很少见。中枢再生的失

败导致人们长期相信大脑和脊髓的损伤在很大程度上是不可逆的，治疗必须仅限于康复措施。

一段时间以来，神经生物学家一直在寻找中枢神经系统和周围神经系统的再生能力差异如此巨大的原因。这

项工作的目标是确定再生的关键障碍，以便克服这些障碍。这些研究已经开始取得成果，现在人们谨慎乐观地

认为，受伤的人类大脑和脊髓具有最终可以被利用的再生能力。

在讨论这些新发育之前，在更广泛的生物学背景下考虑神经再生问题是有帮助的。是外周轴突的再生能力

不寻常，还是中央轴突不能再生？事实上是后者。显然，中央轴突在发育过程中生长良好。更令人惊讶的是，未

成熟哺乳动物的轴突也可以在大脑或脊髓横断后再生。此外，鱼和青蛙等低等脊椎动物的成年中枢神经系统的

再生能力很强，罗杰 · 斯佩里对视神经损伤后视力恢复的研究就是一个例证（第 47 章）。

那么为什么成熟的哺乳动物会失去这种看似重要的修复能力呢？答案可能就在于哺乳动物的大脑有什么无

与伦比的事情，那就是在出生后早期的关键时期，根据经验重塑其基本线路图，使每个人的大脑得到优化，以便

每个个体的大脑都能最佳地应对内部和外部世界的变化和挑战（第 49 章）。一旦发生重塑，就必须对其进行稳

1103

50.3 治疗干预可能促进受伤中枢神经元的再生

Chapter 50 / Repairing the Damaged Brain 1241

Figure 50–4 Axons in the periphery regenerate better than

those in the central nervous system.After sectioning of a

peripheral nerve, the perineural sheath reforms rapidly and

Schwann cells in the distal stump promote axonal growth by

producing trophic and attractant factors and expressing high

levels of adhesive proteins. After sectioning of an axona in the

central nervous system, the distal segment disintegrates and

myelin fragments. In addition, reactive astrocytes and mac-

rophages are attracted to the lesion site. This complex cellular

milieu, termed a glial scar, inhibits axonal regeneration.

prevents an afferent neuron from obtaining sufficient

sustenance from its target cell, the afferent neuron’s

inputs are placed at risk. Such chain reactions help to

explain how injury in one area in the central nervous

system eventually affects regions far from the site of

the injury.

Central Axons Regenerate Poorly After Injury

Central and peripheral nerves differ substantially in

their ability to regenerate after injury. Peripheral nerves

can often be repaired following injury. Although the

distal segments of peripheral axons degenerate, con-

nective tissue elements surrounding the distal stump

generally survive.

Axonal sprouts grow from the proximal stump,

enter the distal stump, and grow along the nerve toward

its targets (Figure 50–4). The mechanisms that drive

this process are related to those that guide embryonic

axons. Chemotropic factors secreted by Schwann cells

attract axons to the distal stump, adhesive molecules

within the distal stump promote axon growth along

cell membranes and extracellular matrices, and inhibi-

tory molecules in the perineural sheath prevent regen-

erating axons from going astray.

Once regenerated peripheral axons reach their tar-

gets, they are able to form new functional nerve end-

ings. Motor axons form new neuromuscular junctions;

autonomic axons successfully reinnervate glands,

blood vessels, and viscera; and sensory axons reinner-

vate muscle spindles. Finally, those axons that lost their

myelin sheaths are remyelinated, and chromatolytic

cell bodies regain their original appearance. Thus, in

all three divisions of the peripheral nervous system—

motor, sensory, and autonomic—the effects of axotomy

are reversible. Peripheral regeneration is not perfect,

however. In the motor system, recovery of strength

may be substantial, but recovery of fine movements is

usually impaired. Some motor axons never find their

targets, some form synapses on inappropriate muscles,

and some motor neurons die. Nevertheless, the regen-

erative capacities in the peripheral nervous system are

impressive.

髓磷脂施旺细胞

周围神经系统

髓磷脂

少突细胞

中枢神经系统

反应性

星形胶质细胞

侵袭

胶质

瘢痕

巨噬细胞

浸润

鞘管

重整

雪旺细胞

促进生长

神经鞘

Kandel-Ch50_1236-1259.indd 1241 12/01/21 9:11 AM

图 50.2.1: 与中枢神经系统中的轴突相比，外周神经系统的轴突再生能力更强。当外周神经被切断后，其神经外

膜能够迅速重建，并且远端断口处的施旺细胞会通过产生促进生长的营养因子和吸引因子，以及高表达粘附蛋

白，来促进轴突的生长。相反，当中枢神经系统中的轴突被切断时，远端部分会发生解体，髓鞘碎片化。此外，

反应性星形胶质细胞和巨噬细胞会被吸引到损伤部位，形成一个复杂的细胞环境，即所谓的胶质瘢痕，这一环

境抑制了轴突的再生。

定。如果另一只眼睛在儿童时期失明，虽然将皮层空间重新分配给一只眼睛显然是有用的，但我们不希望我们

的皮层连接以类似的方式重新排列以响应短暂的不寻常的光照或黑暗。因此，在面对连接性的小扰动时保持恒

定可能会不可避免地导致限制中枢连接响应损伤而再生的能力。从这个角度来看，我们有限的再生能力是一种

浮士德式的交易，我们牺牲了恢复能力来确保维持作为我们卓越智力基础的精确连接回路。

50.3 治疗干预可能促进受伤中枢神经元的再生

在寻找中央轴突再生不良的原因时，一个关键问题是它是否反映了神经元自身无法生长或环境无法支持轴

突生长。阿尔伯特 · 阿瓜约和他的同事在 1980 年代初解决了这个问题。他们将中枢神经干的片段插入周围神经，

并将周围神经的片段插入大脑或脊髓，以了解轴突在面对新环境时会如何反应。

正如预期的那样，从胞体中分离出来的移植物中的轴突迅速退化，留下含有胶质细胞、支持细胞和细胞外

基质的“远端残端”。引人注目的是易位区段附近轴突的行为。脊髓损伤后再生不良的脊髓轴突长入外周移植物

数厘米（图 50.3.1）。同样，在视神经受损后再生不良的视网膜轴突会长到很长的距离，进入放置在其路径上的

外周移植物。相反，如图 50.3.2 所示，外周轴突通过其自身的远端神经干再生良好，但与切断的视神经配对时表

现不佳。

阿瓜约扩展了这些研究，表明来自多个区域的轴突，包括嗅球、脑干和中脑，如果提供合适的环境，都可以

长距离再生。由于我们将在后面的部分讨论的原因，即使是最佳环境也不能完全恢复中央轴突的生长潜力。尽

管如此，这些开创性的实验将注意力集中在抑制再生能力的中央环境成分上，并促使人们深入寻找罪魁祸首。

1104

50.3 治疗干预可能促进受伤中枢神经元的再生

1242 Part VII / Development and the Emergence of Behavior

Figure 50–5 A transplanted peripheral nerve provides

a favorable environment for the regeneration of central

axons.Left: After sectioning of the spinal cord, ascending and

descending axons fail to cross the lesion site. Right: Insertion

of a peripheral nerve graft that bypasses the lesion site pro-

motes regeneration of both ascending and descending axons.

(Adapted from David and Aguayo 1981.)

In contrast, regeneration after injury is poor in

the central nervous system (Figure 50–4). The proxi-

mal stumps of damaged axons can form short sprouts,

but these soon stall and form swollen endings called

“retraction bulbs”, which fail to progress. Long-distance

regeneration is rare. The failure of central regenera-

tion is what led to the long-standing belief that inju-

ries to the brain and spinal cord are largely irreversible

and that therapy must be restricted to rehabilitative

measures.

For some time, neurobiologists have been seeking

the reasons why regenerative capacity in the central

and peripheral nervous systems differs so dramati-

cally. The goal of this work has been to identify the

crucial barriers to regeneration so that they can be

overcome. These studies have begun to bear fruit, and

there is now cautious optimism that the injured human

brain and spinal cord have a regenerative capacity that

can eventually be exploited.

Before discussing these new developments, it is

helpful to consider the problem of neural regenera-

tion in a broader biological context. Is it the ability of

peripheral axons to regenerate that is unusual, or the

inability of central axons to do so? It is in fact the latter.

Obviously, central axons grow well during develop-

ment. More surprisingly, axons in immature mammals

can also regenerate following transection in the brain

or spinal cord. Moreover, regeneration is robust in the

adult central nervous systems of lower vertebrates

such as fish and frogs, as exemplified by the studies of

Roger Sperry on restoration of vision following dam-

age to the optic nerve (Chapter 47).

So why have mature mammals lost this seemingly

important capacity for repair? The answer may lie in

what the mammalian brain can do peerlessly, which

is to remodel its basic wiring diagram in accordance

with experience during critical periods in early post-

natal life, so that each individual’s brain is optimized

to deal with the changes and challenges of internal

and external worlds (Chapter 49). Once remodeling

has occurred, it must be stabilized. Although it is

obviously useful to reassign cortical space to one eye

if the other is blinded in childhood, we would not

want our cortical connections similarly rearranged in

response to a brief period of unusual illumination or

darkness. Maintaining constancy in the face of small

perturbations in connectivity may therefore have the

unavoidable consequence of limiting the ability of cen-

tral connections to regenerate in response to injury. In

this view, our limited regenerative capacity is a Faus-

tian bargain in which we have sacrificed recuperative

power to ensure the maintenance of precisely wired

circuits that underlie our superior intellectual capacity.

Therapeutic Interventions May Promote

Regeneration of Injured Central Neurons

In seeking reasons for the poor regeneration of central

axons, one critical question is whether it reflects an ina-

bility of neurons themselves to grow or an inability of

the environment to support axonal growth. This issue

was addressed by Albert Aguayo and his colleagues

in the early 1980s. They inserted segments of a central

nerve trunk into a peripheral nerve, and segments of a

peripheral nerve into the brain or spinal cord, to find

out how axons would respond when confronted with

a novel environment.

As expected, axons in the grafts, which were sep-

arated from their somata, promptly degenerated, leav-

ing “distal stumps” containing glia, support cells, and

extracellular matrix. What was striking was the behavior

of axons near the translocated segments. Spinal axons

that regenerated poorly following spinal cord injury

grew several centimeters into the peripheral graft

(Figure 50–5). Similarly, retinal axons, which regener-

ated poorly following damage to the optic nerve, grew

long distances into a peripheral graft placed in their path.

周围

神经移植

中枢

神经

系统

Kandel-Ch50_1236-1259.indd 1242 12/01/21 9:11 AM

图 50.3.1: 移植的周围神经为中枢轴突的再生提供了有利的环境。左图：脊髓切片后，上行轴突和下行轴突无法

穿过病变部位。右图：插入绕过损伤部位的周围神经移植物可促进上行轴突和下行轴突的再生

[433]

。

1105

50.3 治疗干预可能促进受伤中枢神经元的再生

Chapter 50 / Repairing the Damaged Brain 1243

Figure 50–6 Peripheral and central nerves differ in their

ability to support axonal regeneration.

A.In the peripheral nervous system, severed axons regrow

past the site of injury. Insertion of a segment of optic nerve

into a peripheral nerve suppresses the ability of the peripheral

nerve to regenerate.

B.In the central nervous system, severed axons typically

fail to regrow past the site of injury. Insertion of a sec-

tion of peripheral nerve into a central nerve tract promotes

regeneration.

Conversely, peripheral axons regenerated well through

their own distal nerve trunk, but fared poorly when

paired with a severed optic nerve (Figure 50–6).

Aguayo extended these studies to show that axons

from multiple regions, including the olfactory bulb,

brain stem, and mesencephalon, could all regenerate

long distances if provided with a suitable environment.

Even an optimal environment cannot fully restore the

growth potential of central axons for reasons we will

discuss in a later section. Nevertheless, these pioneer-

ing experiments focused attention on components of the

central environment that inhibit regenerative ability and

motivated an intensive search for the molecular culprits.

Environmental Factors Support the Regeneration

of Injured Axons

In probing the differences between peripheral and

central growth environments, initial searches were

influenced by the results of experiments performed

by Ramón y Cajal’s student Francisco Tello nearly a

century before Aguayo’s studies. Tello transplanted

segments of peripheral nerves into the brains of exper-

imental animals and found that injured central axons

grew toward the implants, whereas they barely grew

when implants were not available.

This result implied that peripheral cells provide

growth-promoting factors to the injured areas, factors

normally absent from the brain. Ramón y Cajal rea-

soned that central nerve pathways lacked “substances

able to sustain and invigorate the indolent and scanty

growth” similar to those provided by peripheral path-

ways. Numerous studies over the succeeding century

identified constituents of peripheral nerves that are

potent promoters of neurite outgrowth. These include

components of Schwann cell basal laminae, such as

laminin, and cell adhesion molecules of the immuno-

globulin superfamily. In addition, cells in denervated

切除周围神经切除视神经

再生再生不良

切除和移植

周围神经

切除和移植

视神经

再生无再生

脊髓肌肉视网膜

顶盖

A 周围神经系统

（运动神经和感觉神经）

B 中枢神经系统

（视神经）

Kandel-Ch50_1236-1259.indd 1243 12/01/21 9:11 AM

图 50.3.2: 外周神经和中枢神经支持轴突再生的能力不同。A. 在周围神经系统中，被切断的轴突会在受伤部位重

新长出。将一段视神经插入周围神经会抑制周围神经再生的能力。B. 在中枢神经系统中，被切断的轴突通常无

法通过受伤部位重新生长。将一段周围神经插入中枢神经束可促进再生。

1106

50.3 治疗干预可能促进受伤中枢神经元的再生

50.3.1 环境因素支持受伤轴突的再生

在探索外围和中心生长环境之间的差异时，最初的搜索受到了拉蒙 · 卡哈尔的学生弗朗西斯科 · 特略进行

的实验结果的影响，比阿瓜约的研究早了将近一个世纪。特略将周围神经的片段移植到实验动物的大脑中，发

现受伤的中央轴突向植入物生长，而当没有植入物时，它们几乎不生长。

这一结果表明外周细胞为受伤区域提供了生长促进因子，而这些因子在大脑中通常是不存在的。拉蒙 · 卡

哈尔推断，中枢神经通路缺乏“能够维持和促进惰性和稀疏生长的物质”，类似于外周通路所提供的物质。在接

下来的一个世纪里，大量研究确定了周围神经的成分是神经突长出的有效促进剂。这些包括施旺细胞基底层的

成分，例如层粘连蛋白和免疫球蛋白超家族的细胞粘附分子。此外，去神经的远端神经残端中的细胞开始产生

第 46 章中描述的神经营养蛋白和其他营养分子。这些分子共同滋养神经元并引导胚胎神经系统中轴突的生长，

因此它们也促进轴突的再生。相比之下，中枢神经元组织是这些分子的贫乏来源，含有少量层粘连蛋白和低水

平的营养分子。因此，在胚胎中，中枢和周围神经系统都提供了促进轴突生长的环境。但只有外围环境才能在成

年期保留这种能力，或者能够在受伤后有效地恢复这种能力。

这种观点的实际意义是，用促进生长的分子补充中央环境可能会改善再生。为此，研究人员将神经营养蛋

白注入损伤区域或插入富含细胞外基质分子（如层粘连蛋白）的纤维，作为轴突生长的支架。在一些尝试中，施

旺细胞本身，或经过工程改造可分泌营养因子的细胞，已被移植到损伤部位。在许多这样的情况下，受伤的轴突

比在控制条件下生长得更广泛。然而，再生仍然有限，轴突通常无法延伸很远的距离。更重要的是，功能恢复很

少。

50.3.2 髓磷脂的成分抑制神经突生长

是什么导致如此有限的再生？部分解释是，被切断的中央轴突所处的环境不仅缺乏生长促进因子，而且富

含生长抑制因子，其中一些来自髓鞘。在培养中，中枢而非外周髓鞘的片段有效地抑制了共培养的中枢或外周

神经元的神经突生长。相反，如图 50.3.3 所示，在经过治疗以防止脊髓中髓磷脂形成的大鼠中，损伤后脊髓轴突

侧枝的发芽得到增强。

1244 Part VII / Development and the Emergence of Behavior

Figure 50–7 Myelin inhibits regeneration of central

axons.(Adapted, with permission, from Schwegler, Schwab,

and Kapfhammer 1995.)

A.Sensory fibers normally extend rostrally in a myelin-rich

spinal cord.

B.Right dorsal root fibers were sectioned in 2-week-old normal

rats. Regeneration of the fibers was assessed histochemically

20 days later. The central branches of the sectioned axons

degenerated, leaving a portion of the spinal cord denervated.

Little regeneration occurred in the myelin-rich cord.

C.Some littermates received local x-irradiation to block myeli-

nation. In these animals, sensory fibers that entered the cord

through neighboring uninjured roots sprouted new collaterals

following denervation.

distal nerve stumps begin to produce neurotrophins

and other trophic molecules of the sort described in

Chapter 46. Together, these molecules nourish neurons

and guide growing axons in the embryonic nervous

system, so it makes sense that they also promote the

regrowth of axons. By contrast, central neuronal tis-

sue is a poor source of these molecules, containing lit-

tle laminin and low levels of trophic molecules. Thus,

in the embryo, both central and peripheral nervous

systems provide environments that promote axon out-

growth. But only the peripheral environment retains

this capacity in adulthood or is able to regain it effec-

tively following injury.

The practical implications of this view are that

supplementing the central environment with growth-

promoting molecules might improve regeneration. To

this end, investigators have infused neurotrophins

into areas of injury or inserted fibers rich in extracel-

lular matrix molecules such as laminin to serve as scaf-

fold for axonal growth. In some attempts, Schwann

cells themselves, or cells engineered to secrete trophic

factors, have been grafted into sites of injury. In many

of these cases, injured axons grow more extensively

than they do under control conditions. Yet regenera-

tion remains limited, with axons generally failing to

extend long distances. More important, functional

recovery is minimal.

Components of Myelin Inhibit Neurite Outgrowth

What accounts for such disappointingly limited regen-

eration? One part of the explanation is that the envi-

ronment encountered by severed central axons is not

only poor in growth-promoting factors but also rich in

growth-inhibiting factors, some of which are derived

from myelin. In culture, fragments of central but not

peripheral myelin potently inhibit neurite outgrowth

from co-cultured central or peripheral neurons. Con-

versely, sprouting of spinal axon collaterals following

injury is enhanced in rats treated to prevent myelin

formation in the spinal cord (Figure 50–7).

These findings implied that although both central

and peripheral environments might contain a supply

of growth-promoting elements, central nerves also

contain inhibitory components. The fact that myelin

inhibits neurite growth may seem peculiar, but not if

we consider that myelination normally occurs postna-

tally, after axon extension is largely complete.

Searches for the inhibitory components of central

myelin turned up an embarrassment of riches. Several

classes of molecules that occur at higher levels in cen-

tral myelin compared to peripheral myelin are able to

inhibit neurite outgrowth when presented to cultured

neurons. The first to be discovered was identified when

an antibody generated against myelin proteins proved

正

常

富含髓鞘的脊髓

有限再生

无髓鞘脊髓

的再生

髓磷脂无髓磷脂

感觉

纤维

Kandel-Ch50_1236-1259.indd 1244 12/01/21 9:11 AM

图 50.3.3: 髓磷脂抑制中央轴突的再生

[434]

。A. 感觉纤维通常在富含髓磷脂的脊髓中向头端延伸。B. 在两周大的

正常大鼠中，右侧背根纤维被切断。20 天后，通过组织化学方法评估了这些纤维的再生情况。被切断的轴突的

中枢分支发生了退化，导致脊髓的一部分失去了神经支配。在富含髓鞘的脊髓区域，几乎没有发生再生。C. 一

些同窝仔接受局部 X 射线照射以阻止髓鞘形成。在这些动物中，通过邻近未受伤的根部进入脐带的感觉纤维在

去神经支配后长出了新的侧枝。

1107

50.3 治疗干预可能促进受伤中枢神经元的再生

这些发现表明，尽管中枢和外周环境都可能含有促进生长的元素，但中枢神经也含有抑制成分。髓鞘抑制

神经突生长的事实可能看起来很奇怪，但如果我们考虑到髓鞘形成通常发生在出生后，即轴突延伸基本完成之

后，就不是这样了。

寻找中枢髓磷脂的抑制成分发现了一大堆难题。与外周髓磷脂相比，中央髓磷脂中出现的几类分子在呈现

给培养的神经元时能够抑制神经突生长。当针对髓磷脂蛋白产生的抗体被证明能够部分中和髓磷脂抑制神经突

长出的能力时，发现了第一个发现。使用这种抗体分离相应的抗原产生了现在称为 Nogo 的蛋白质。另外 2 种蛋

白质，髓磷脂相关糖蛋白和髓鞘少突胶质细胞糖蛋白，最初作为髓鞘的主要成分被分离出来，也被发现可以抑

制某些神经元类型的生长。

有趣的是，如图 50.3.4 所示，Nogo、髓磷脂相关糖蛋白和髓鞘少突胶质细胞糖蛋白与常见的膜受体 NogoR 和

PirB 结合。NogoR 以及与生长抑制有关的相关受体，如 LINGO，都与神经营养蛋白受体 p75 相互作用（第 46 章）。

这种相互作用将 p75 从促进生长的受体转变为抑制生长的受体。也许是因为有太多的生长抑制因子和受体，在

缺少其中任何一种的突变小鼠中，中央轴突的再生并没有大大增强。然而，许多抑制成分会触发激活 RhoA 的相

同细胞内信号通路，从而刺激 Rho 激酶（ROCK）；ROCK 反过来导致生长锥坍塌并阻断神经突生长所需的肌动

蛋白和微管蛋白聚合。目前的研究正在探索干扰该共享通路是否可以一次性抵消许多抑制剂的影响。

50.3.3 损伤引起的疤痕阻碍轴突再生

髓鞘碎片并不是受伤大脑或脊髓中生长抑制物质的唯一来源。如前所述，星形胶质细胞在受伤后被激活并

增殖，获得在受伤部位产生疤痕组织的反应性星形胶质细胞的特征。疤痕形成是一种适应性反应，有助于限制

损伤的大小、重建血脑屏障并减少炎症。

但疤痕本身以 2 种方式阻碍再生：通过机械干扰轴突生长和通过疤痕内细胞产生的蛋白质的生长抑制作用。

如图 50.3.4 所示，这些抑制剂中最主要的是一类硫酸软骨素蛋白多糖，它由反应性星形胶质细胞大量产生，并

通过与轴突上的酪氨酸磷酸酶受体相互作用直接抑制轴突延伸。因此，注意力集中在通过注入一种叫做软骨素

酶的酶来溶解神经胶质疤痕的方法，这种酶可以分解硫酸软骨素蛋白多糖上的糖链。这种治疗促进了动物的轴

突再生和功能恢复。在受伤后不久、疤痕形成之前服用消炎、减少疤痕的药物，尤其是泼尼松龙，也是有益的。

减少炎症和减少疤痕形成的药物，特别是泼尼松龙，如果在受伤后不久、疤痕形成之前服用，也是有益的。

50.3.4 内在增长计划促进再生

到目前为止，我们已经强调了外周轴突和中央轴突的局部环境之间的差异。然而，环境差异不能完全解释

中央轴突再生不良的原因。尽管它们可以在外周神经中再生，但在沿着相同路径行进时，中枢轴突的生长情况

远不如外周轴突。因此，成人中央轴突的再生能力可能不如外周轴突。

为支持这一想法，组织培养实验表明，中枢神经元的生长潜力会随着年龄的增长而降低，而成熟的外周神

经元在有利的环境中会稳健地延伸轴突。对这种差异的一个可能解释是被认为对最佳轴突伸长至关重要的蛋白

质表达的变化。一个例子是 43 kDa 生长相关蛋白，或神经生长相关蛋白-43。这种蛋白质在胚胎中枢神经元和外

周神经元中以高水平表达。在外周神经元中，成熟度水平仍然很高，并且在轴突切开术后增加更多，而在中枢神

经元中，其表达随着发育的进行而降低。协调轴突生长程序所需的转录因子也在发育过程中以高水平表达，然

后在成熟过程中下调。

中央轴突再生能力的降低是否可逆？两组研究提供了希望。其中之一涉及所谓的“条件性损伤”。回想一下，

背根神经节中的初级感觉神经元有一个分叉的轴突，一个外围分支延伸到皮肤、肌肉或其他目标，一个中央分

支进入脊髓。外围分支在受伤后再生良好，而中央分支再生较差。然而，如图 50.3.5 所示，如果外围分支在中央

分支受损前几天受损，中央分支将成功再生。不知何故，先前的伤害或条件性损伤会激活轴突生长程序。

负责中央分支再生的生长程序的一个组成部分似乎是环磷酸腺苷。这种第二信使分子激活酶，进而促进神

经突生长。当神经元最初形成回路时，环磷酸腺苷的水平很高；它们在中枢神经元而非外周神经元中在出生后

下降。在某些情况下，增加环磷酸腺苷或通常由环磷酸腺苷激活的蛋白质的供应可以促进损伤后中枢轴突的再

生。因此，增加环磷酸腺苷水平或激活环磷酸腺苷靶点的药物被积极考虑作为脊髓损伤后的治疗剂。

1108

50.3 治疗干预可能促进受伤中枢神经元的再生

Chapter 50 / Repairing the Damaged Brain 1245

Figure 50–8 Myelin and glial scar com-

ponents that inhibit regeneration of

central axons.(Adapted from Yiu and He

2006.)

Left: Myelin contains the proteins Nogo-

A, oligodendrocyte-myelin glycoprotein

(OMgp), and myelin-associated glycopro-

tein (MAG). All three proteins are exposed

when myelin breaks down. They can bind

to the receptor protein NogoR, which can

associate with the neurotrophin receptor

p75, as well as an immunoglobulin-like

receptor protein PirB. Inactivation of PirB

results in a modest enhancement of

corticospinal axon regeneration. Right:

Chondroitin sulphate proteoglycans

(CSPG) are major components of the glial

scar and are thought to suppress axon

regeneration through interaction with the

receptor tyrosine phosphatase PTP-sigma,

which activates intracellular mediators

such as Rho and ROCK.

to be capable of partially neutralizing myelin’s ability

to inhibit neurite outgrowth. Use of this antibody to

isolate the corresponding antigen yielded the protein

now called Nogo. Two other proteins, myelin-associated

glycoprotein (MAG) and oligodendrocyte-myelin

glycoprotein (OMgp), initially isolated as major com-

ponents of myelin, have also been found to inhibit the

growth of some neuronal types.

Intriguingly, Nogo, MAG, and OMgp bind to

common membrane receptors, NogoR and PirB

(Figure 50–8). NogoR, as well as related receptors

such as LINGO that have been implicated in growth

inhibition, all interact with the neurotrophin receptor

p75 (Chapter 46). This interaction converts p75 from

a growth-promoting to a growth-inhibiting receptor.

Perhaps because there are so many growth inhibitory

factors and receptors, regeneration of central axons is

not greatly enhanced in mutant mice lacking any one

of them. However, many of the inhibitory compo-

nents trigger the same intracellular signaling pathway

in which RhoA is activated, thereby stimulating Rho

kinase (ROCK); ROCK in turn leads to the collapse of

growth cones and blocks actin and tubulin polymeri-

zation required for neurite growth. Current studies are

p75

NogoRPirB

硫酸软骨素

蛋白多糖

ROCK

Rho

轴突生长

抑制

反应性

星形胶质细胞

受损少突胶质细胞

PTP-Sigma

髓鞘少突

胶质细胞糖蛋白

Nogo-A

Kandel-Ch50_1236-1259.indd 1245 12/01/21 9:11 AM

髓磷脂相关

糖蛋白

图

50.3.4

: 抑制中央轴突再生的髓磷脂和神经胶质疤痕成分

[435]

。左图：髓磷脂含有蛋白质

Nogo-A

、

髓鞘少突

胶质细胞糖蛋白和髓磷脂相关糖蛋白。当髓磷脂分解时，所有 3 种蛋白质都会暴露出来。它们可以结合受体蛋

白 NogoR，后者可以与神经营养蛋白受体 p75 以及免疫球蛋白样受体蛋白 PirB 结合。PirB 的失活导致皮层脊

髓轴突再生的适度增强。右图：硫酸软骨素蛋白多糖是胶质瘢痕的主要成分，被认为通过与受体酪氨酸磷酸酶

PTP-sigma 相互作用来抑制轴突再生，PTP-sigma 激活细胞内介质，如 Rho 和 ROCK。

1109

50.3 治疗干预可能促进受伤中枢神经元的再生

中枢

轴突

外周

轴突

感觉

神经元

A 未损伤

B 中枢性损害

再生

区域

损伤部位

无再生

先前的外周病变

促进再生

环磷酸腺苷

神经生长

相关蛋白-43

图 50.3.5: 条件性损伤促进初级感觉神经元轴突中央分支的再生。脊髓损伤后，损伤部位以外的中央分支几乎没

有再生。然而，如果轴突的外围分支在中央分支受损之前被切开，则后者会生长到病变部位之外。这种“条件性

损伤”的影响可以通过提高周围分支中环磷酸腺苷或生长相关蛋白神经生长相关蛋白-43 的水平来模拟。

1110

50.3 治疗干预可能促进受伤中枢神经元的再生

第二组研究操纵发育调节的内在因素来恢复成人的再生能力。例如，损伤有时会导致睫状神经营养因子等

细胞因子的形成，这些细胞因子通过激活涉及称为 JAK 和 STAT 的分子的信号通路来促进生长，这些分子会进

入细胞核并调节生长程序。然而，在成人中，该通路被一种称为细胞因子信号通路抑制因子 3 的蛋白质所抑制。

如图 50.3.6A 所示，删除小鼠中的细胞因子信号通路抑制因子 3 基因可解除抑制并增强细胞因子促进受损轴突再

生的能力。

野生型

细胞因子信号通路抑制因子

突变体

蛋白酪氨酸磷酸酶基因

突变体

蛋白酪氨酸磷酸酶基因

细胞因子信号通路抑制因子

双突变体

细胞因子信号通路抑制因子 3

糖蛋白

130

无

再生

细胞因子信号通路抑制因子 3

两面神激酶

信号转导和

转录激活因子

再生

野生型

蛋白酪氨酸磷酸酶基因

无

再生

蛋白酪氨酸磷酸酶基因

哺乳动物雷帕

霉素靶蛋白

再生

睫状

神经营

养因子

蛋白酪氨酸磷酸酶基因

细胞因子信号通路抑制因子 3

增加的

再生

视网膜神经节细胞

哺乳动物雷帕

霉素靶蛋白

哺乳动物雷帕

霉素靶蛋白

睫状

神经营

养因子

两面神激酶-信号转

导和转录激活因子

睫状

神经营

养因子

图 50.3.6: 调节视神经轴突再生的信号通路。A. 视神经中视网膜神经节细胞轴突的再生通常受到几个基因的神

经元表达的限制。一种编码细胞因子信号通路抑制因子 3，它阻断睫状神经营养因子结合其受体糖蛋白 130 的能

力，从而阻断睫状神经营养因子促进再生。在细胞因子信号通路抑制因子 3 突变小鼠中，睫状神经营养因子的

环境水平足以改善视神经再生。消除糖蛋白 130 和细胞因子信号通路抑制因子 3 会阻碍再生能力。添加额外的

睫状神经营养因子可增强细胞因子信号通路抑制因子 3 突变小鼠的再生能力。B. 另一个基因编码蛋白酪氨酸磷

酸酶基因，它通过调节能量代谢的哺乳动物雷帕霉素靶蛋白通路阻断信号。因此，蛋白酪氨酸磷酸酶基因突变

小鼠的再生得到增强。C. 因为细胞因子信号通路抑制因子 3 和蛋白酪氨酸磷酸酶基因调节不同的生长促进信号，

缺乏这 2 个基因的突变小鼠表现出比任何一个突变体更强的再生能力

[436]

。

同样，涉及激酶哺乳动物雷帕霉素靶蛋白的信号通路调节能量代谢，促进轴突再生所需的合成代谢生长促

进状态。然而，随着中枢神经元的成熟，哺乳动物雷帕霉素靶蛋白被下调，并被称为蛋白酪氨酸磷酸酶基因的磷

酸酶进一步抑制。如图 50.3.6B 所示，类似于细胞因子信号通路抑制因子 3 和两面神激酶-信号转导和转录激活

因子

信号，小鼠中

蛋白酪氨酸磷酸酶基因

基因的缺失促进了视神经或脊髓损伤后的轴突再生。此外，

细胞因子

1111

50.4 受伤大脑中的神经元死亡，但可以产生新的神经元

信号通路抑制因子 3 和蛋白酪氨酸磷酸酶基因的丢失比任何一个的丢失都更能刺激再生。尽管它们的多重作用

使得细胞因子信号通路抑制因子 3 或蛋白酪氨酸磷酸酶基因不太可能成为有用的治疗靶点，但它们调节的信号

通路为设计可以增强再生的药物提供了多个起点。

50.3.5 完整轴突形成新的连接可导致损伤后功能的恢复

到目前为止，我们已经讨论了旨在增强受损中枢轴突有限再生能力的干预措施。另一种策略侧重于即使没

有明显的切割轴突再生也能在受伤后发生的重要但不完全的功能恢复。如果能够理解这种功能有限恢复的基础，

就有可能加强它。

为应对损伤而重新排列现有的连接可能有助于功能的恢复。我们已经了解到，轴突切开术会导致受损神经

元的输入和目标发生变化。尽管其中许多变化对功能有害，但有些变化是有益的。特别是，中枢神经系统在受伤

后可以自发地进行适应性重组，帮助其恢复功能。例如，许多脊髓外伤都会发生下行皮层脊髓通路横断后，皮层

不能再向损伤部位下方的运动神经元传递指令。然而，如图 50.3.7 所示，在数周后，位于病变头端的完整皮层脊

髓轴突开始长出新的末端分支，并在其轴突围绕病变延伸的脊髓中间神经元上形成突触，从而形成有助于有限

恢复功能的脊柱内迂回。

Chapter 50 / Repairing the Damaged Brain 1249

Figure 50–11 Function can be recovered after spinal cord

injury through reorganization of spinal circuits.Severed cor-

ticospinal axons can reestablish connections with motor neu-

rons by sprouting axon collaterals that innervate propriospinal

interneurons whose axons bypass the lesion and contact motor

neurons located caudal to the lesion site. (Adapted from Bareyre

et al. 2004.)

to improve recovery following injury therefore need

to consider survival of neurons and not simply the

regrowth of axons. Since neuronal death is a frequent

consequence of other neural insults, such as stroke and

neurodegenerative disease, improved ways of retain-

ing or replacing neurons would have broad utility.

The loss of cells following injury is not unique to

the nervous system, although in other tissues, new cells

are often effective at repairing damage. This regenera-

tive capacity is most dramatic in the hematopoietic sys-

tem, where a few stem cells can repopulate the entire

adaptive immune system. In contrast, it has long been

believed that the generation of neurons is complete by

birth. Because of this, approaches to regeneration have

often focused on finding ways to spare neurons that

would otherwise die.

This traditional view has changed, prompted ini-

tially by Joseph Altman’s discovery in the 1960s that

neurogenesis continues into adulthood in some parts

of the mammalian brain. Since this finding challenged

fundamental tenets of prevailing dogma, the idea that

new neurons could form in postnatal rodents was met

with skepticism for three decades.

Eventually, however, the application of better cell

labeling technologies amply supported Altman’s con-

clusion and showed that it also applies to nonhuman

primates and even, in a limited way, to humans. We

are now confident that new neurons are added to the

dentate gyrus of the hippocampus and to the olfac-

tory bulb throughout life, although the rate of addition

declines with age. Some of the newborn cells in the

dentate gyrus of the adult hippocampus die soon after

they are born and others become glial cells, but a sub-

stantial minority differentiate into granule cells that

are indistinguishable from those born at embryonic

stages (Figure 50–12). New neurons are also added to

the adult olfactory bulb. They are generated near the

surface of the lateral ventricles, far from the bulb itself,

and then migrate to their destination (Figure 50–13).

In both cases, the new neurons extend processes,

form synapses, and become integrated into functional

circuits. Thus, neurons born at embryonic stages are

gradually replaced by later-born neurons, so that the

total number of neurons in these regions of the brain

is maintained.

The properties of neurons born in mature ani-

mals are not completely understood, but they appear

able to recapitulate many of the properties of neurons

that arise in the embryo. When the generation of new

neurons in the adult is prevented, certain behaviors

mediated by the olfactory bulb and hippocampus are

degraded. Conversely, some behavioral alterations are

accompanied by alterations in the tempo of adult neu-

rogenesis. Adult neurogenesis can be decreased in ani-

mal models of depression and chronic stress, whereas

enrichment of the habitat of an animal or an increase

in the physical activity of otherwise sedentary rodents

can increase the generation of new neurons.

What cells give rise to adult-born neurons? The

principle that embryonic neurons and glia arise from

multipotential progenitors also applies to neurons

born in adults. Stem cells are the source of neurons in

the adult as well as the embryo. They are likely derived

from radial glia, which also serve as a source of

中间神经元

运动

神经元

病变部位

Kandel-Ch50_1236-1259.indd 1249 12/01/21 9:11 AM

图 50.3.7: 脊髓损伤后可以通过重组脊髓回路恢复功能。切断的皮层脊髓轴突可以通过发芽轴突侧枝来重新建立

与运动神经元的连接，轴突侧枝支配神经元中间神经元，其轴突绕过病变并接触位于病变部位尾部的运动神经

元

[437]

。

类似的功能重组实例已在运动皮层和脑干中得到证实。这些补偿反应证明了神经系统的潜在可塑性。神经

系统重新连接自身的能力在出生后早期的关键时期最为活跃，但在成年期的创伤事件中可以恢复（第 49 章）。

如何提高中枢神经系统的重布线能力？移植物对实验动物的一些有益影响可能反映了完整轴突的重组，而

不是横断轴突的再生。随着神经系统的可塑性得到更好的理解，促进回路特定变化的治疗策略可能成为可能。也

许最有前途的是一种方法，其中促进生长的细胞或分子干预与导致回路重新布线的行为疗法相结合。

50.4 受伤大脑中的神经元死亡，但可以产生新的神经元

无法长出新的轴突绝不是可能降临在受伤神经元身上的最糟糕的命运。对于许多神经元，轴突切开术会导

致细胞死亡。因此，改善损伤后恢复的努力需要考虑神经元的存活，而不仅仅是轴突的再生。由于神经元死亡是

其他神经损伤（例如中风和神经退行性疾病）的常见后果，因此保留或替换神经元的改进方法将具有广泛的用

途。

损伤后细胞的丢失并不是神经系统独有的，尽管在其他组织中，新细胞通常可以有效修复损伤。这种再生

能力在造血系统中最为显著，其中一些干细胞可以重新填充整个适应性免疫系统。相比之下，长期以来人们一

1112

50.4 受伤大脑中的神经元死亡，但可以产生新的神经元

直认为神经元的生成在出生时就已完成。正因为如此，再生方法往往侧重于寻找挽救那些原本会死亡的神经元

的方法。

这种传统观点已经改变，最初是由于约瑟夫 · 奥特曼在 1960 年代发现哺乳动物大脑的某些部分的神经形成

会持续到成年期。由于这一发现挑战了流行教条的基本原则，30 年来，新神经元可以在出生后的啮齿动物中形

成的想法遭到怀疑。

然而，最终，更好的细胞标记技术的应用充分支持了奥特曼的结论，并表明它也适用于非人类灵长类动物，

甚至在有限的情况下也适用于人类。我们现在确信，新的神经元会在整个生命过程中添加到海马齿状回和嗅球

中，尽管添加速度会随着年龄的增长而下降。如图 50.4.1 所示，成年海马齿状回中的一些新生细胞在出生后不

久就死亡，其他的则变成神经胶质细胞，但有相当一部分分化为颗粒细胞，与胚胎阶段的细胞无法区分。新的神

经元也被添加到成人的嗅球中。如图 50.4.2 所示，它们在侧脑室表面附近产生，远离嗅球本身，然后迁移到它们

的目的地。在这 2 种情况下，新神经元都会扩展过程、形成突触并整合到功能回路中。因此，在胚胎阶段出生的

神经元逐渐被后来出生的神经元所取代，因此大脑这些区域的神经元总数得以维持。

1250 Part VII / Development and the Emergence of Behavior

Figure 50–12 Neurons born in the germinal zone of the

dentate gyrus in adult rodents are integrated into hip-

pocampal circuits. The diagrams on the left show the path-

ways of neuronal differentiation and integration into dentate

gyrus circuits. The images on the right show newly generated

neurons and their dendritic arbors labeled with a virus express-

ing green fluorescence protein. (Micrographs reproduced, with

permission, from F. Gage.)

neurons during embryonic development (Chapter 46).

A subset of these cells exit the cell cycle during gesta-

tion, become quiescent, and take up residence near the

ventricular surface. In adulthood, they are activated,

reenter the cell cycle, and give rise to neurons.

Although so far adult neurogenesis has not been

directly linked to repair of damaged tissue, its discov-

ery has influenced research on recovery from injury in

two important ways. First, the findings that endoge-

nously generated neurons can differentiate and extend

processes through the thicket of adult neuropil, and

can be integrated into functional circuits, led research-

ers to test the idea that the same could be true for trans-

planted neurons or precursors. Second, since neural

precursors can be induced to divide and differenti-

ate, strategies designed to augment this innate ability

are now being considered, with the goal of producing

neurons in large enough numbers to replace those lost

to injury or neurodegenerative disease. As we describe

below, these ideas have progressed over the past few

decades from science fiction to efforts that are tantaliz-

ingly close to clinical tests.

Therapeutic Interventions May Retain or

Replace Injured Central Neurons

Transplantation of Neurons or Their Progenitors

Can Replace Lost Neurons

For many years, neurologists have transplanted devel-

oping neurons into experimental animals to see if the

new neurons could reverse the effects of injury or dis-

ease. These attempts have had promising results in a

few cases.

激增整合分化

阿

蒙角3

苔藓纤维

通路

谢弗旁路

齿状

区

穿通

通路

阿

蒙角1

Kandel-Ch50_1236-1259.indd 1250 12/01/21 9:11 AM

图 50.4.1: 成年啮齿动物海马体齿状回的生发区中新生成的神经元会被整合进海马回的神经网络中。左侧的图示

描绘了神经元的分化路径及其如何融入齿状回路的过程。右侧的图像展示了利用表达绿色荧光蛋白的病毒标记

的新生成神经元及其树突分支。

成熟动物中出生的神经元的特性尚不完全清楚，但它们似乎能够概括胚胎中出现的神经元的许多特性。当

成人体内新神经元的产生受到阻止时，由嗅球和海马体介导的某些行为就会退化。相反，一些行为改变伴随着

成人神经形成速度的改变。在抑郁症和慢性压力的动物模型中，成年神经形成可能会减少，而动物栖息地的丰

富或久坐不动的啮齿动物的身体活动的增加可以增加新神经元的产生。

哪些细胞会产生成年神经元？胚胎神经元和神经胶质细胞来自多能祖细胞的原理也适用于成人出生的神经

元。干细胞是成人和胚胎神经元的来源。它们可能源自放射状神经胶质细胞，放射状神经胶质细胞在胚胎发育

1113

50.4 受伤大脑中的神经元死亡，但可以产生新的神经元

Chapter 50 / Repairing the Damaged Brain 1251

Figure 50–13 The origin and fate of neurons born

in the adult ventricular zone.(Adapted from Tavazoie et al.

2008.)

A.Neuroblasts develop in an orderly progression from astro-

cytic stem cells via a population of cells within a local niche

close to blood vessels in the subventricular zone. (Abbreviation:

CSF, cerebrospinal fluid.)

B.Neuroblasts differentiate into immature neurons that migrate

to the olfactory bulb using astrocytes as guides. They crawl

along each other in a process called chain migration.

C.On arrival in the olfactory bulb, immature neurons

differentiate into granule cells and periglomerular cells, two

classes of olfactory bulb interneurons. (Image reproduced, with

permission, from A. Mizrahi.)

成神经细胞

过渡放大细胞

干细胞星

形胶质细胞

B 迁移

C 整合

脑脊液

血管

室管膜细胞

嗅球

齿状回

嘴侧

迁移流

A 神经发生

脑室下区

星形胶质细胞

未成熟

神经元

颗粒

细胞

球周

细胞

Kandel-Ch50_1236-1259.indd 1251 12/01/21 9:11 AM

图 50.4.2: 成人脑室区神经元的起源和命运

[438]

。A. 神经祖细胞以有序的方式从星形胶质干细胞发育而来，这一

过程涉及局部微环境中的细胞群体，该群体靠近侧脑室下区血管。B. 成神经细胞分化成未成熟的神经元，这些

神经元使用星形胶质细胞作为向导迁移到嗅球。它们在称为链式迁移的过程中相互爬行。C. 到达嗅球后，未成

熟的神经元分化为颗粒细胞和球周细胞，两类嗅球中间神经元。

1114

50.5 治疗干预可能会保留或替换受伤的中枢神经元

过程中也是神经元的来源（第 46 章）。这些细胞的一个子集在妊娠期间退出细胞周期，变得静止，并在心室表

面附近居住。在成年期，它们被激活，重新进入细胞周期，并产生神经元。

虽然到目前为止，成人神经形成与受损组织的修复没有直接联系，但它的发现在 2 个重要方面影响了损伤

恢复的研究。首先，内源性产生的神经元可以通过成年神经细胞的丛林区分和扩展过程，并可以整合到功能回

路中，这一发现促使研究人员测试了移植的神经元或前体也是如此的想法。其次，由于可以诱导神经前体分裂

和分化，因此现在正在考虑旨在增强这种先天能力的策略，其目标是产生足够数量的神经元以替代因受伤或神

经退行性疾病而丢失的神经元。正如我们在下面描述的，这些想法在过去几十年里已经从科幻小说发展到非常

接近临床试验的成果。

50.5 治疗干预可能会保留或替换受伤的中枢神经元

50.5.1 神经元或其祖细胞的移植可以替代丢失的神经元

多年来，神经学家一直将发育中的神经元移植到实验动物体内，以观察新神经元是否可以逆转损伤或疾病

的影响。这些尝试在一些案例中取得了可喜的成果。

一种是替代在帕金森病中死亡的多巴胺能细胞。如图 50.5.1 所示，当移植到纹状体中时，这些神经元将多

巴胺释放到它们的目标上，而不需要长出长轴突或形成精细的突触。另一种方法是将不成熟的抑制性中间神经

元从产生它们的神经节隆起（第 46 章）移植到皮层，在那里它们成熟并形成突触。通过增强抑制，这些神经元

减弱了抑制驱动力不足发挥作用的疾病的表现，例如癫痫和焦虑症。

不幸的是，将这些方法应用于人类患者一直充满困难。一个是难以获得足够数量和足够纯度的发育中的神

经元。其次，通过引入新基因来修改神经元以提高它们在新环境中发挥作用的机会一直具有挑战。第三，在许多

情况下，移植的神经元已经太成熟，无法正确分化或有效整合到功能回路中。

这些障碍可以通过将神经前体移植到成年大脑中来克服，在那里它们可以在适宜的环境中继续分化成神经

元。几类前体细胞已成功移植，包括神经干细胞和定向前体细胞。胚胎干细胞已取得一些初步成功。这些细胞

来源于早期胚泡阶段的胚胎，可以产生身体的所有细胞。因为它们可以在培养中无限分裂，所以可以产生大量

细胞，诱导分化，然后移植。

最近，如图 50.5.2 所示，通过对皮肤成纤维细胞进行分子重编程以创建诱导的多能性干细胞，该技术得到

了增强。

这些细胞与胚胎干细胞相比具有明显的优势；它们的生产不需要胚胎，有效地绕过了阻碍使用人类胚胎干

细胞进行研究的实际、政治和伦理问题的雷区。诱导的多能性干细胞的另一个优势是它们可以从个体患者自身

的皮肤细胞中产生，巧妙地避免了免疫不相容的问题。还可以通过在移植前修复缺陷基因来对培养的诱导的多

能性干细胞进行基因修饰。

由于胚胎干细胞和诱导的多能性干细胞具有产生任何细胞类型的潜力，因此在移植之前，它们的分化必须

沿着特定的培养通路进行引导。如图 50.5.2 所示，现在已经设计出从胚胎干细胞和诱导的多能性干细胞生成特

定类别的神经前体、神经元和神经胶质细胞的方法。例如，如图 50.5.3 所示，可以生成具有在肌萎缩性侧索硬化

症中丧失的脊髓运动神经元的许多或全部特性的神经元，或者生成在帕金森病中从纹状体中丧失的多巴胺能神

经元，然后将这些神经元移植到脊髓或大脑中。

尽管需要克服许多障碍，但使用胚胎干细胞和诱导的多能性干细胞衍生神经元的临床试验正在进行中。此

外，这些细胞还被用于化学筛选，以鉴定能够抵消人类神经退行性疾病背后的细胞缺陷化合物。

50.5.2 刺激损伤区域的神经形成可能有助于恢复功能

如果在成人受伤后，可以刺激内源性神经元前体产生能够替代那些已经丢失的神经元的神经元呢？最近的

两组研究结果表明，这个想法并非遥不可及。

1115

50.5 治疗干预可能会保留或替换受伤的中枢神经元

1252 Part VII / Development and the Emergence of Behavior

Figure 50–14 Loss of dopaminergic (DA) neurons in

Parkinson disease can be treated by grafting embryonic

cells into the putamen.

A.In the healthy brain, dopaminergic projections from the sub-

stantia nigra (SN) innervate the putamen, which in turn activates

neurons in the globus pallidus (GP). Pallidal outputs to the brain

and spinal cord facilitate movement. The image below shows

melanin-rich dopaminergic neurons in human substantia nigra.

B.In Parkinson disease, the loss of dopaminergic neurons in

the substantia nigra deprives the putamen–globus pallidus

pathways of their drive. The image beneath the diagram shows

the virtual absence of melanin-rich dopaminergic neurons in the

substantia nigra of an individual with Parkinson disease.

C.Direct injection of embryonic dopaminergic neurons into the

putamen reactivates the globus pallidus output pathways. The

image below shows tyrosine hydroxylase expression in the cell

bodies and axons of embryonic mesencephalic dopaminergic

neurons grafted into the putamen of a human patient. (Image

reproduced, with permission, from Kordower and

One is to replace dopaminergic cells that die in

Parkinson disease. When transplanted into the stria-

tum, these neurons release dopamine onto their tar-

gets without the need to grow long axons or form

elaborate synapses (Figure 50–14). Another is to

transplant immature inhibitory interneurons from

the ganglionic eminences in which they are pro-

duced (Chapter 46) to the cortex, where they mature

and form synapses. By enhancing inhibition, these

neurons attenuate the manifestations of disorders in

which insufficient inhibitory drive plays a role, such

as epilepsy and anxiety.

Unfortunately, application of these methods to

human patients has been fraught with difficulties. One

is the difficulty of obtaining and growing develop-

ing neurons in sufficient numbers and with sufficient

purity. Second, it has been challenging to modify neu-

rons by introducing new genes so as to improve their

chances of functioning in a new environment. Third, in

many cases, the grafted neurons are already too mature

A 正常

脊髓

苍白球

壳核

B 帕金森病 C 恢复

黑质

苍白球

壳核

黑质

多巴胺能

神经元的

注射

Kandel-Ch50_1236-1259.indd 1252 12/01/21 9:11 AM

图 50.5.1: 帕金森病中多巴胺能神经元的缺失可以通过将胚胎细胞移植到壳核中来治疗。A. 在健康的大脑中，来

自黑质的多巴胺能投射支配壳核，进而激活苍白球中的神经元。大脑和脊髓的苍白球输出促进运动。下图显示

了人类黑质中富含黑色素的多巴胺能神经元。B. 在帕金森病中，黑质中多巴胺能神经元的丧失剥夺了壳核-苍白

球通路的驱动力。图表下方的图像显示帕金森病患者的黑质中几乎没有富含黑色素的多巴胺能神经元。C. 将胚

胎多巴胺能神经元直接注射到壳核中会重新激活苍白球输出通路。下图显示了移植到人类患者壳核中的胚胎中

脑多巴胺能神经元的细胞体和轴突中的酪氨酸羟化酶表达

[439]

。

1116

50.5 治疗干预可能会保留或替换受伤的中枢神经元

Chapter 50 / Repairing the Damaged Brain 1253

Figure 50–15 Induced pluripotent stem cells can be repro-

grammed to generate precursors of many neuronal and

glial types. The precursors can then be transplanted into the

brain or spinal cord, where cells complete their differentiation

and integrate into functional circuits. (Abbreviations: DA,

dopamine; DG, dentate gyrus; NPC, neural progenitor cell;

OPC, oligodendrocyte progenitor cell.) (Adapted, with permission,

to differentiate properly or to integrate effectively into

functional circuits.

These obstacles can be overcome by transplanting

neural precursors into the adult brain where they can

go on to differentiate into neurons in a hospitable envi-

ronment. Several classes of precursors have been trans-

planted successfully, including neural stem cells and

committed precursors. Some initial success has been

obtained with embryonic stem (ES) cells. These cells are

derived from early blastocyst stage embryos and can

give rise to all cells of the body. Because they can divide

indefinitely in culture, large numbers of cells can be

generated, induced to differentiate, and then engrafted.

More recently, this technology has been enhanced

by the molecular reprogramming of skin fibroblast

cells to create induced pluripotent stem (iPS) cells

(Figure 50–15). These cells have a distinct advantage

over ES cells; embryos are not required for their pro-

duction, effectively bypassing a minefield of practi-

cal, political, and ethical concerns that have hindered

research using human ES cells. Another advantage of

iPS cells is that they can be generated from an indi-

vidual patient’s own skin cells, neatly avoiding issues

of immunological incompatibility. It is also possible to

genetically modify the iPS cells in culture by repairing

a defective gene before transplantation.

Because ES and iPS cells have the potential to gener-

ate any cell type, it is essential that their differentiation

be guided along specific pathways in culture before they

are transplanted. Methods for generating specific classes

of neural precursors, neurons, and glial cells from ES

and iPS cells have now been devised (Figure 50–15).

神经元

亚型

骨形态发生蛋白/

TGFβ / WNT

SHH

骨形态发生蛋白/

TGFβ

SHH/WNT/ FGF8 WNT3a

骨形态发生蛋白/

TGFβ

/ SHH

成纤维细胞生长因子

PDGF-A

骨形态发生蛋白/

TGFβ / SHH

处理

祖细胞

背前脑

神经祖细胞

腹前脑

神经祖细胞

中脑底板

神经祖细胞

海马

神经祖细胞

髓鞘形成

少突胶质细胞

中脑多巴胺能

神经元

皮层γ-氨基丁酸能

神经元

皮层谷氨酸能

神经元

海马齿状回

颗粒细胞

人诱导

多能干细胞

Kandel-Ch50_1236-1259.indd 1253 12/01/21 9:11 AM

图 50.5.2: 诱导多能干细胞可以重新编程以产生许多神经元和神经胶质类型的前体。然后可以将前体移植到大脑

或脊髓中，细胞在那里完成分化并整合到功能回路中

[440]

。

1117

50.5 治疗干预可能会保留或替换受伤的中枢神经元

1254 Part VII / Development and the Emergence of Behavior

Figure 50–16 Induced pluripotent stem cells

derived from an individual with amyotrophic

lateral sclerosis (ALS) can differentiate into

spinal motor neurons.Fibroblasts from the

skin of a patient with ALS were used to generate

induced pluripotent stem (iPS) cells, which were

then directed to a motor neuron fate (see Figure

50–15). These cells can be used to analyze mech-

anisms that underlie motor neuron loss in ALS.

The images at right show (from top to bottom)

cultured fibroblasts, an iPS cell clump, and differ-

entiated motor neurons expressing characteristic

nuclear transcription factors (green) and axonal

proteins (red). (Micrographs reproduced, with

permission, from C. Henderson, H. Wichterle,

G. Croft, and M. Weygandt.)

For example, it is possible to generate neurons that pos-

sess many or all of the properties of the spinal motor

neurons that are lost in amyotrophic lateral sclerosis

(Figure 50–16) or to generate the dopaminergic neurons

lost from the striatum in Parkinson disease and then to

engraft such neurons into the spinal cord or brain.

Although many hurdles need to be overcome,

clinical trials using ES and iPS cell-derived neurons

are underway. In addition, these cells are being used in

chemical screens to identify compounds that counteract

the cellular defects that underlie human neurodegenera-

tive disease.

Stimulation of Neurogenesis in Regions of Injury

May Contribute to Restoring Function

What if, following injury in adults, endogenous neu-

ronal precursors could be stimulated to produce

neurons capable of replacing those that have been lost?

Two sets of recent findings suggest that this idea is not

so far-fetched.

First, precursors capable of forming neurons in

culture have been isolated from many parts of the

adult nervous system, including the cerebral cortex

and spinal cord, even though neurogenesis in adults

is ordinarily confined to the olfactory bulb and hip-

pocampus. This diversion of cell fate led to the idea

that neurogenesis in the adult occurs in only a few

sites, because only they contain appropriate permissive

or stimulatory factors. This hypothesis has spurred a

search for such factors, in the hope that they could be

used to render a larger range of sites capable of sup-

porting neurogenesis.

Second, in a few cases, the generation of new neu-

rons can be stimulated by traumatic or ischemic injury

(akin to stroke), even in areas such as the cerebral cortex

收集

皮肤成纤维细胞

将皮肤成纤维细胞

重新编程为

诱导的多能性干细胞

视黄酸

刺猬

肌萎缩

侧索硬化

患者

皮肤成纤维细胞

运动

神经元

诱导的

多能性干细胞

Kandel-Ch50_1236-1259.indd 1254 12/01/21 9:11 AM

图 50.5.3: 来自患有肌萎缩侧索硬化的个体的诱导多能干细胞可以分化为脊髓运动神经元。如图 50.5.2 所示，来

自肌萎缩侧索硬化患者皮肤的成纤维细胞用于生成诱导的多能性干细胞，然后将其定向至运动神经元命运。这

些细胞可用于分析肌萎缩侧索硬化中运动神经元丢失的机制。右图显示（从上到下）培养的成纤维细胞、诱导

的多能性干细胞细胞团和表达特征性核转录因子（绿色）和轴突蛋白（红色）的分化运动神经元。

1118

50.6 要点

首先，能够在培养物中形成神经元的前体已从成人神经系统的许多部分分离出来，包括大脑皮层和脊髓，尽

管成人的神经形成通常局限于嗅球和海马体。这种细胞命运的转变导致了这样的想法，即成人的神经形成只发

生在少数几个部位，因为只有它们包含适当的允许或刺激因素。这一假设激发了对此类因素的研究，希望它们

可以用于呈现更大范围的能够支持神经形成的位点。

其次，在少数情况下，即使在大脑皮层或脊髓等神经形成通常不会发生的区域，外伤或缺血性损伤（类似于

中风）也会刺激新神经元的产生。中风和受伤后恢复较差的事实表明，自发代偿性神经形成（如果发生在人类

身上）不足以进行组织修复。然而，损伤诱导的神经形成在实验动物中以多种方式得到增强。其中之一，生长因

子的施用促进了在培养物中生长的祖细胞的神经元产生。另一方面，保留分裂能力的胶质细胞，例如视网膜中

的米勒胶质细胞或皮层中的星形胶质细胞，被重新编程以分化为神经元。如果此类干预措施适用于人类，则需

要更换的神经元范围将大大增加。

50.5.3 非神经元细胞或其祖细胞的移植可以改善神经元功能

脑损伤后神经元以外的细胞会丢失。损失最严重的是少突胶质细胞，即围绕中央轴突形成髓鞘的细胞。髓

鞘的剥离在外伤后很长时间内仍在继续，并导致可能未直接受伤的轴突功能逐渐丧失。

尽管成人大脑和脊髓能够产生新的少突胶质细胞并替换丢失的髓鞘，但在许多情况下，这种产生不足以恢

复功能。由于几种常见的神经系统疾病，尤其是多发性硬化症，都伴随着严重的脱髓鞘状态，因此人们对为神经

系统提供额外的少突胶质细胞前体以增加髓鞘再生产生了浓厚的兴趣。

神经干细胞、多能祖细胞、胚胎干细胞和诱导的多能性干细胞细胞不仅可以产生神经元，还可以产生非神

经细胞，包括少突胶质细胞及其直接前体细胞。事实上，目前，人类胚胎干细胞正被导入少突胶质细胞祖细胞，

并植入实验动物受伤的脊髓中。如图 50.5.4 所示，分化为少突胶质细胞的移植细胞可增强髓鞘再生并显著提高

实验动物的运动能力。

50.5.4 功能恢复是再生疗法的目标

我们需要记住，如果这些轴突不能与它们的靶细胞形成功能性突触，那么更换中枢神经元或增强轴突再生

的努力将毫无用处。因此，关于成人轴突再生的相同基本问题也适用于突触形成：它会发生吗？如果不会，为什

么不会？

解决这些问题一直很困难，因为实验性损伤后的轴突再生通常很差，以至于轴突永远无法到达适当的目标

区域。然而，本章前面讨论的几项研究提供了希望，即在致密的成人神经细胞内可能形成突触。事实上，受伤后

再生的轴突分支可以在附近的目标上形成突触。例如，如图 50.5.5A 所示，阿瓜约和他的同事发现，当视网膜轴

突通过已移植到视神经的周围神经时，它们能够重新长成上丘。值得注意的是，如图 50.5.5B 所示，当眼睛被照

亮时，一些丘神经元会发射动作电位，表明功能性突触连接已经重新建立。如上所述，最近的研究通过增强其内

在生长程序促进了切断的轴突的再生，并观察到一些功能恢复。

同样，内源性产生或由研究人员植入的神经元可以形成和接收突触。因此，有理由相信，如果可以诱导受伤

的轴突再生，或者提供新的神经元来替换丢失的轴突，它们将以有助于恢复丢失的功能和行为的方式连接起来。

50.6 要点

1. 当轴突被横切时，远端节段发生退化，这一过程称为华勒氏变性。近端节段和细胞体也会发生变化，受

损神经元的突触输入和目标也会发生变化。

2. 长期以来，人们一直认为华勒氏变性是远端节段被剥夺细胞体营养的被动和不可避免的结果，但它是一

个主动的、受调节的过程并不为人所知。称为烟酰胺单核苷酸腺嘌呤转移酶 1 和 SARM1 的基因是控制该过程的

核心信号通路的关键组成部分。对该通路的干预可以减缓甚至停止退化。

3. 轴突在受伤后可以再生并形成新的突触，但在哺乳动物中，外周轴突的再生比中央轴突的再生更为广泛

和有效。

1119

50.6 要点

Chapter 50 / Repairing the Damaged Brain 1255

Figure 50–17 Restoration of

myelination in the central nervous

system by transplanted oligo-

dendrocyte stem cells.In rodents

with demyelinated axons, grafts of

oligodendrocyte precursor cells can

restore myelination to near normal.

Sections through central nerve tracts

are shown in the images at right.

(Adapted, with permission, from

Franklin and ffrench-Constant 2008.

or spinal cord in which neurogenesis normally fails to

occur. The fact that recovery after stroke and injury is

poor demonstrates that spontaneous compensatory

neurogenesis, if it occurs in humans, is insufficient for

tissue repair. However, injury-induced neurogenesis

has been enhanced in experimental animals in several

ways. In one, administration of growth factors pro-

motes neuronal production from progenitors grown in

culture. In another, glial cells that retain the capacity to

divide, such as Müller glia in the retina or astrocytes

in the cortex, are reprogrammed to differentiate into

neurons. If such interventions could be adapted to

humans, the range of neurons subject to replacement

would be greatly increased.

Transplantation of Nonneuronal Cells or Their

Progenitors Can Improve Neuronal Function

Cells other than neurons are lost after brain injury.

Among the most profound losses are those of oligo-

dendrocytes, the cells that form the myelin sheath

around central axons. The stripping of myelin contin-

ues long after traumatic injury and contributes to pro-

gressive loss of function of axons that may not have

been injured directly.

Although the adult brain and spinal cord are capa-

ble of generating new oligodendrocytes and replacing

lost myelin, this production is insufficient to restore

function in many cases. Since several common neuro-

logical diseases, most notably multiple sclerosis, are

accompanied by a profound state of demyelination,

there is strong interest in providing the nervous sys-

tem with additional oligodendrocyte precursors in

order to augment remyelination.

Neural stem cells, multipotential progenitors, ES

cells, and iPS cells can give rise not only to neurons

but also to nonneural cells, including oligodendrocytes

and their direct precursors. Indeed, at present, human

ES cells are being channeled into oligodendrocyte pro-

genitor cells and implanted into injured spinal cords of

experimental animals. Transplanted cells that differen-

tiate into oligodendrocytes enhance remyelination and

substantially improve the locomotor ability of experi-

mental animals (Figure 50–17).

Restoration of Function Is the Aim of

Regenerative Therapies

We need to bear in mind that efforts to replace central

neurons or to enhance the regeneration of their axons

脱髓鞘

正常

髓鞘再生

Kandel-Ch50_1236-1259.indd 1255 12/01/21 9:11 AM

图 50.5.4: 通过移植的少突胶质细胞干细胞恢复中枢神经系统的髓鞘形成。在轴突脱髓鞘的啮齿动物中，少突胶

质前体细胞的移植物可以使髓鞘形成恢复到接近正常水平。右图显示了通过中枢神经束的切片

[441]

。

1120

50.6 要点

1256 Part VII / Development and the Emergence of Behavior

Figure 50–18 Regenerated retinal ganglion axons in the

optic nerve can form functional synapses.(Adapted, with

AAAS.)

A.A segment of optic nerve in an adult rat was removed, and

a segment of sciatic nerve was grafted in its place. The other

end of the sciatic nerve was attached to the superior collicu-

lus. Some retinal ganglion cell axons regenerated through the

sciatic nerve and entered the superior colliculus.

B.Once the axons of the retinal ganglion neurons had regen-

erated, recordings were made from the superior colliculus.

Flashes of light delivered to the eye elicited action potentials

in collicular neurons, demonstrating that at least some regen-

erated axons had formed functional synapses.

would be of little use if these axons were unable to

form functional synapses with their target cells. The

same fundamental questions asked about axon regen-

eration in adults therefore apply to synaptogenesis:

Can it happen, and if not, why not?

It has been difficult to address these questions

because axonal regeneration following experimentally

induced injury is usually so poor that the axons never

reach appropriate target fields. However, several of the

studies discussed earlier in this chapter offer hope that

synapse formation is possible within the dense adult

neuropil. In fact, axon branches that regenerate follow-

ing injury can form synapses on nearby targets. For

example, Aguayo and his colleagues found that retinal

axons were able to regrow into the superior colliculus

when they were channeled through a peripheral nerve

that had been grafted into the optic nerve (Figure

50–18A). Remarkably, some collicular neurons fired

action potentials when the eye was illuminated, show-

ing that functional synaptic connections had been

reestablished (Figure 50–18B). More recent studies have

promoted regeneration of severed axons by enhancing

their intrinsic growth programs, as described above,

and observed some restoration of function.

Likewise, neurons that arise endogenously or

are implanted by investigators can form and receive

synapses. Thus, there is reason to believe that if injured

axons can be induced to regenerate, or new neurons

supplied to replace lost ones, they will wire up in ways

that help restore lost functions and behaviors.

Highlights

1. When axons are transected, the distal segment

degenerates, a process called Wallerian degen-

eration. The proximal segment and cell body also

undergo changes, as do the injured neuron’s syn-

aptic inputs and targets.

2. It was long thought that Wallerian degeneration

was a passive and inevitable consequence of the

distal segment being deprived of sustenance

from the cell body, but it is not known to be an

active, regulated process. Genes called NMNAT

and SARM1 are key components of a core sign-

aling pathway that controls the process. Inter-

vention in the pathway can slow or even halt

degeneration.

3. Axons can regenerate and form new synapses

following injury, but in mammals, regeneration is

far more widespread and effective in peripheral

axons than in central axons.

刺激

嫁接

上丘

视

神

经

（

移除）

Kandel-Ch50_1236-1259.indd 1256 12/01/21 9:11 AM

图 50.5.5: 视神经中再生的视网膜神经节轴突可以形成功能性突触

[442]

。A. 移除成年大鼠的一段视神经，并在其

位置移植一段坐骨神经。坐骨神经的另一端与上丘相连。一些视网膜神经节细胞轴突通过坐骨神经再生并进入

上丘。B. 一旦视网膜神经节神经元的轴突再生，就从上丘进行记录。传送到眼睛的闪光在丘脑神经元中引起动

作电位，表明至少一些再生的轴突已经形成了功能性突触。

1121

50.6 要点

4. 外周轴突和中央轴突反应不同的一个关键因素是，受伤的中央轴突所处的环境不利于生长。它既缺乏周

围神经通路中存在的营养因子，又含有周围神经中不存在的生长抑制因子。

5. 抑制再生的结构包括在华勒变性后持续存在的髓鞘碎片和在损伤部位形成神经胶质疤痕的星形胶质细

胞。髓鞘中的抑制因子包括 Nogo 和髓鞘相关糖蛋白。星形胶质细胞分泌的抑制因子包括硫酸软骨素蛋白聚糖。

6. 由于在发育过程中活跃的生长程序下调，成人中枢神经元生长的内在能力下降也阻碍了中枢再生。恢复

或解除抑制生长通路的干预措施，例如两面神激酶-信号转导和转录激活因子和哺乳动物雷帕霉素靶蛋白信号，

可以促进再生。

7. 然而，重要的是要注意，受伤后再生失败可能与关键时期结束时发生的连接稳定有关。例如，主要发生

在关键期末期的髓鞘形成可能具有防止突触连接进一步大规模重排的次要作用。因此，需要谨慎确保旨在促进

损伤后恢复的治疗不会最终促进适应不良回路的形成。

8. 损伤后恢复功能的另一种方法是利用完整轴突形成新连接的能力，产生适应性回路，在一定程度上补偿

因损伤而丧失的轴突。

9. 所有神经形成都发生在妊娠期间或妊娠后不久的传统观点现在已经被新神经元在整个生命过程中的几个

大脑区域中诞生的发现所修正。这些神经元来自常驻干细胞，可以整合到功能回路中。

10. 能够形成新神经元的细胞也存在于大脑和脊髓的许多其他区域，但仍处于静止状态。尝试通过提供生长

因子或引入促生长基因（转录重编程）来激活它们，可以利用它们在受伤后或神经退行性疾病中的潜力。

11. 另一种神经元替代方法是植入发育中的神经元。尽管有时在实验动物中将胎儿神经元用于此目的，但更

有用的来源可能是源自

胚胎干细胞

或

诱导的多能性干细胞

的神经元。它们可以大量生长，必要时进行基因改造，

并进行处理以分化成特定的神经元类型。使用这种方法的临床研究现已开始。

1122